Program Director/Principal Investigator (Last, First, Middle): Culley, Deborah J ABSTRACT Surgery triggers a cascade of humoral, cellular, and subcellular events involved in inflammation and its resolution. These profound immune responses have a major influence on postoperative outcomes, and many complications of surgery are due to dysregulated inflammation. Older persons have more surgery than younger ones and are especially prone to serious postoperative morbidity. The immune system becomes dysregulated with age and this dysfunction contributes to the pathogenesis of age-related diseases, including cognitive decline. Poor cognition is a potent and consistent risk factor for adverse surgical outcomes; we have shown it doubles the risk of postoperative delirium and halves the chance of being discharged home after elective joint replacement surgery. We have also demonstrated that between 22-40% of elective surgical patients ? 70 years of age are probably cognitively impaired at the time of surgery. Therefore, the combination of poor preoperative cognition and poor surgical outcomes is both common and clinically important. Yet, it is not known how poor cognition increases susceptibility to postoperative morbidity, and the situation is little studied. We propose that poor preoperative cognition signifies a state of immune disequilibrium / dysfunction that shapes the immune response to surgery and increases postoperative morbidity. We will test this proposition by examining humoral (plasma inflammatory and resolution mediators; Aim 1), cellular (monocyte transcriptome and function; Aim 2), and subcellular (circulating extracellular vesicle [EV] concentration, cargo, and function; Aim 3) components of inflammation in cognitively screened patients having surgical procedures common in old age (total joint replacement; spine surgery), with delirium and discharge to place other than home as clinical and patient- centered-outcomes, respectively. Preliminary results showing cognition- or outcome-related differences in the ratio of circulating proinflammatory and proresolution mediators, the transcriptome of blood-borne monocytes, and the distribution of plasma extracellular vesicles support our model. This research is innovative because the impact of preoperative cognition on the immunology of surgical recovery has not been studied previously, it will test novel pathogenic mechanisms (monocyte dysfunction, EVs) for preoperative cognition-driven risk and use state-of-the-art ex vivo and in vitro methods (multiplexed gene panels), and may identify a molecular signature for adverse postoperative outcomes and, thereby, potential therapeutic targets. Given the magnitude and importance of the clinical problem being addressed, this is a high impact proposal that may increase the precision and personalization of surgical care and improve outcomes for older patients. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page